Synthesis and Biological Evaluation of (3/4-(pyrimidin-2-ylamino)benzoyl)-based Hydrazine-1-carboxamide/carbothioamide Derivatives As Novel RXRα Antagonists

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2020 Apr 1

PMID 32223461

Citations 3

Authors

Jingbo Qin

Jie Liu

Chunxiao Wu

Jianwen Xu

Bowen Tang

Kaiqiang Guo

Xiaohui Chen

Weihao Liu

Tong Wu

Hu Zhou

Meijuan Fang

Zhen Wu

Affiliations

Soon will be listed here.

Abstract

Abnormal alterations in the expression and biological function of retinoid X receptor alpha (RXRα) have a key role in the development of cancer. Potential modulators of RXRα as anticancer agents are explored in growing numbers of studies. A series of (4/3-(pyrimidin-2-ylamino)benzoyl)hydrazine-1-carboxamide/carbothioamide derivatives are synthesised and evaluated for anticancer activity as RXRα antagonists in this study. Among all synthesised compounds, shows strong antagonist activity (half maximal effective concentration (EC) = 1.68 ± 0.22 µM), potent anti-proliferative activity against human cancer cell lines HepG2 and A549 cells (50% inhibition of cell viability (IC) values < 10 µM), and low cytotoxic property in normal cells such as LO2 and MRC-5 cells (IC values > 100 µM). Further bioassays indicate that inhibits 9-cis-RA-induced activity in a dose-dependent manner, and selectively binds to RXRα-=LΒD with submicromolar affinity (Kd = 1.20 × 10 M). induces time-and dose-dependent cleavage of poly ADP-ribose polymerase, and significantly stimulates caspase-3 activity, leading to RXRα-dependent apoptosis. Finally, molecular docking studies predict the binding modes for RXRα-LBD and .

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